Abstract Liver Cancer is a deadly disease, lacking any effective treatment options. Molecular genetics underlying this deadly malignancy remains poorly understood. The Hippo tumor suppressor cascade is an evolutionally conserved pathway that controls organ size, tissue regeneration, stem cell self-renewal, and tumor development. Recent genetic studies support the importance of Hippo pathway during liver cancer development. However, the precise functional role of Yap and TAZ, the two transcriptional co-activators downstream of Hippo kinases, and how they interact with other onocgenic pathways during hepatic carcinogenesis have not been characterized. In our recent studies, we found that Yap and TAZ are both highly expressed in a subset of human liver cancer samples. Importantly, we found that while Yap or TAZ alone is unable to induce liver tumor formation in vivo, overexpression of Yap or TAZ synergizes with activated AKT signaling to accelerate hepatic carcinogenesis in mice. The tumor cells show increased cell proliferation as well as activated Notch and Wnt/-catenin pathways. Furthermore, we found that both Yap and TAZ are activated in multiple mouse liver tumor models, including HCC induced by AKT/Ras or c-Myc oncogenes. Overexpression of Lats2, which inhibits nuclear localization and promotes degradation of Yap or TAZ, strongly inhibited AKT/Ras and c-Myc induced hepatic carcinogenesis in mice, supporting a critical role of Hippo pathway in regulating oncogene induced liver tumor development. In this competing renewal application, we will systematically characterize the functional roles of Yap and TAZ during liver cancer development. We propose three aims. In Aim One, we will elucidate the molecular mechanisms underlying accelerated liver tumor development induced by the co-expression of AKT/Yap or AKT/TAZ. In Aim Two, we will define the role of Yap and TAZ in AKT/Ras induced liver tumor development. And in Aim Three, we will characterize the functional contribution of Yap and TAZ in c-Myc induced hepatic carcinogenesis. Altogether, in the proposed application, we will apply sophisticated mouse genetic approaches with the goal to uncover the functional significance of Yap and TAZ transcriptional co-activators during hepatic carcinogenesis. The study will also provide novel mechanistic insight into the genetic and biochemical crosstalk among the key oncogenic pathways, including Yap/TAZ, AKT/mTOR, Wnt/-catenin, Notch and c-Myc cascades during liver cancer development. The study will likely provide strong evidence to support the development of small molecules or siRNA based therapeutics against Yap or TAZ as novel treatment strategies for liver cancer.